We found that mice deficient in both FcgRIIB, which predisposes to systemic lupus erythematosus (SLE), and CD300f exhibit an accelerated and more lethal course of autoimmune disease, associated with splenomegaly, autoantibody production and tissue pathology. Thus, the impaired clearance of apoptotic cells(AC) associated with CD300f deficiency exacerbates the development of autoimmunity. CD300f expression clearly promotes AC phagocytosis by primary macrophages and cell lines, in a manner that is largely dependent on the capacity of CD300f to signal. We showed that AC recognition strongly enhances the phosphorylation of five intracellular CD300f tyrosines, predominantly on Y276, which leads to p85a recruitment to CD300f. We present the details about how CD300f functions in AC engulfment,highlighting the involvement of PI3K and actin rearrangements. We propose that CD300f accumulates at AC contact sites that will evolve into the invaginating part of phagocytic cups and where following phosphorylation in response to PS recognition, it recruits p85a and activates PI3K. This, in turn, results in PI3K phosphorylating PI(4,5)P2 to PI(3,4,5)P3. As PI(4,5)P2 associates with gelsolin, profilin and other proteins regulating actin cytoskeleton, the absence of PI(4,5)P2 could lead to the clearance of cortical F-actin from the invaginating part of the cup during CD300f-mediated phagocytosis. This eliminates a physical barrier created by the actin meshwork and decrease the membrane rigidity, thereby allowing for easier membrane deformation and AC internalization. At the same time, the increase in PI(3,4,5)P3 levels would serve to activate the small GTPase Rac/Cdc42 pathway to promote F-actin assembly along the protruding part of the phagocytic cups for membrane extension, required for phagocytic cup closure. The fact that latrunculin treatment blocks CD300f-mediated protrusion extension and phagosome sealing without interruption of membrane cup formation supports the notion that F-actin is unnecessary for the initial membrane cup formation, but is required for further cup extension and phagosome sealing. The phosphorylation of the other four CD300f intracellular tyrosines (Y241, Y289, Y303 and Y325) leads to inhibition of phagocytosis by inhibiting PI3K activation, as evidenced by changes in Akt phosphorylation. A mutation of any one of these four tyrosines resulted in the increased AC phagocytosis, further indicating that those tyrosine-based motifs are indeed involved in the initiation of inhibitory signals. Most likely, SHP1 is the phosphatase involved in the inhibitory signaling, as it associates with CD300f in J774 and HeLa cells, and SHP1 overexpression decreases CD300f-mediated AC phagocytosis in a dose-dependent manner. In agreement, SHP1 has been shown to be recruited to Fc receptor-mediated phagosomes and negatively regulate phagocytosis. The maximal association between CD300f and SHP1 has been reported to require several tyrosines (Y241, Y289 and Y325). Exactly how the multiple tyrosines cooperatively associate with SHP1 for the regulation of phagocytosis needs further study. IL-4 receptor a chain, the common receptor chain for IL-4 and IL-13, is a critical component in IL-4 and IL-13-mediated signaling and subsequent effector functions, such as those observed in type 2 inflammatory responses. The existence of intrinsic pathways capable of amplifying IL-4Ra-induced responses was unknown. We identified CD300f as an IL-4-induced molecule in macrophages. Subsequent analyses demonstrated that CD300f was colocalized and physically associated with IL-4Ra. Using Cd300f-/- cells and receptor cross-linking experiments, we established that CD300f amplified IL-4Ra-induced responses by augmenting IL-4/IL-13-induced signaling, mediator release, and priming. Consistently, IL-4 and aeroallergen-treated Cd300f-/- mice displayed decreased IgE production, chemokine expression, and inflammatory cell recruitment. Impaired responses in Cd300f-/- mice were not due to the inability to generate a proper Th2 response, because IL-4/IL-13 levels were markedly increased in allergen-challenged Cd300f-/- mice, a finding that is consistent with decreased cytokine consumption. Finally, CD300f expression was increased in monocytes and eosinophils obtained from allergic rhinitis patients. Collectively, our data highlight a previously unidentified role for CD300f in IL-4Ra-induced immune cell responses. These data provide new insights into the molecular mechanisms governing IL-4Ra-induced responses, and may provide new therapeutic tools to target IL-4 in allergy and asthma. In summary, our data demonstrates that CD300f recognizes PS exposed on the AC surface, and transduces signals for PI3K activation and F-actin remodeling, thereby promoting AC phagocytosis. Consequently, a deficiency in CD300f leads to impaired AC clearance and exacerbates the development of autoimmune disease. Moreover, CD300f regulates the function of the IL-4 receptor. We showed that mouse CD300b (CLM7/LMIR5), expressed on myeloid cells, recognizes outer membrane-exposed phosphatidylserine (PS) and does not, as previously reported, directly recognize TIM1 or TIM4. CD300b accumulates in phagocytic cups along with F-actin at apoptotic cell contacts, thereby facilitating their engulfment. The CD300b-mediated activation signal is conveyed through CD300b association with the adaptor molecule DAP12, and requires a functional DAP12 ITAM motif. Binding of apoptotic cells promotes the activation of the PI3K-Akt kinase pathway in macrophages, while silencing of CD300b expression diminishes PI3K- Akt kinase activation and impairs efferocytosis. Collectively, our data show that CD300b recognizes PS as a ligand, and regulates the phagocytosis of apoptotic cells via the DAP12 signaling pathway.